tbuckley/cabot-search huggingface dataset:
Overall survival of patients with chronic obstructive pulmonary disease receiving immunotherapy for non-small cell lung cancer: A population-based analysis in Ontario, Canada.
Authors: Sze Wah Samuel Chan, John R. Goffin, Gregory Russell Pond
Journal: Journal of Clinical Oncology (2022)

e21172 Background: Outside of clinical trial eligibility criteria, there is limited data to guide the selection of patients with non-small cell lung cancer (NSCLC) for immune checkpoint inhibitor (ICI) therapy. Chronic obstructive pulmonary disease (COPD) and lung cancer are associated, independent of smoking history, with a common background of chronic inflammation. Previous studies have demonstrated that COPD is a negative prognostic marker for NSCLC, but the clinical benefit of ICI in patients with NSCLC and COPD is unknown. Methods: A population-level administrative data analysis of Ontario patients was performed through the Institute of Clinical Evaluative Sciences (ICES) Data Analytic Services. All patients with NSCLC diagnosed between Jan 2010 and Dec 2020 and treated with immune-checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab) were included. Demographics, comorbidity and marginalization scores, and COPD status were extracted along with outcome information. Overall survival (OS) was estimated using the Kaplan-Meier method, and compared between patients with or without COPD using Cox proportional hazards regression. The frequency of patients requiring hospitalization and duration of treatment was also estimated and compared using the chi-square and Wilcoxon rank-sum test. Results: 73331 NSCLC patients were identified, of which 4.5% (n = 3285) patients received ICI. COPD patients were less likely to receive immunotherapy (3.8% vs. 5.1%, p &lt; 0.001). Among those receiving an ICI, 41% (n = 1362) of patients had a diagnosis of COPD prior to NSCLC diagnosis. Median (95% CI) OS was 17.3 (16.6 to 18.2) months for patients with COPD and 16.9 (16.2 to 17.8) for patients with no known COPD, which was not significantly different in univariate (hazard ratio = 0.96, 95% CI = 0.89 to 1.04, p = 0.35) or multivariate analysis (HR = 0.96, 95% CI = 0.89 to 1.05, p = 0.40). The 5-year survival was also similar between both groups (6.7% vs. 6.5%). The rate of hospitalization within 6 months (18.4% vs 18.0%, p = 0.82) and the duration of immunotherapy treatment (median = 80 vs 71 days p = 0.23) did not differ for the COPD vs. non-COPD groups. Conclusions: Despite an expectation of frailty, our data suggest that NSCLC patients with COPD receiving ICI maintained similar durations of treatment and similar rates of hospitalization, with no significant difference in survival time, compared with those without COPD. While a treatment selection bias cannot be excluded in this non-randomized dataset, our data suggest that a diagnosis of COPD itself should not be considered a contraindication to immune checkpoint inhibitor use in NSCLC.
Molecular analysis of circulating tumor DNA (ctDNA) in patients (pts) with <i>EGFR </i>exon 20 insertion-positive (ex20ins+) advanced NSCLC treated with mobocertinib.
Authors: Sylvie Vincent, Zhenqiang Su, Veronica Bunn, Adarsh Joshi, Ziji Yu, Sampurna Chatterjee, Minakshi Guha, Pingkuan Zhang
Journal: Journal of Clinical Oncology (2022)

9108 Background: ctDNA is an important tool to diagnose and monitor mutations in pts with non–small cell lung cancer (NSCLC). We evaluated epidermal growth factor receptor gene ( EGFR) ex20ins mutations in tumor vs plasma samples, assessed changes in EGFR ex20ins variant allele frequency (VAF) with mobocertinib treatment and correlation with response, and identified potential emerging variants of acquired resistance. Methods: Tumor tissue samples were collected at baseline (BL) from pts with EGFR ex20ins+ advanced NSCLC receiving mobocertinib 160 mg QD in a phase 1/2 study (NCT02716116); plasma samples were collected at BL, after 2 treatment cycles (Cycle 3, Day 1 [C3D1]) and at disease progression/end of treatment (DP/EOT). ctDNA samples were analyzed by next-generation sequencing for EGFR ex20ins to determine concordance rate detection between tissue and plasma ctDNA at BL. Changes in VAF for EGFR ex20ins from BL were analyzed at C3D1 and DP/EOT by confirmed response (RECIST v1.1) to mobocertinib per independent review committee. Emerging variants at DP/EOT were evaluated by elimination of germline variants seen in healthy populations (gnomAD databases and 1000 Genomes) and nonharmful variants predicted by PolyPhen and SIFT tools or annotated as benign in ClinVar database. Results: BL EGFR ex20ins mutations were detected by ctDNA sequencing in 29 of 38 pts (76%) with tissue-confirmed EGFR ex20ins+ NSCLC. VAFs for EGFR ex20ins significantly decreased at C3D1 in mobocertinib-treated pts with confirmed partial response (PR; P=0.0057) or stable disease (SD; P=0.0016), but not in pts with progressive disease (PD; P=0.14) (Table). ctDNA at EOT/DP analysis identified numerous genetic variants; EGFR, TP53, and DNMT3A were the most common genes with emerging variants. Twelve emerging missense mutations were identified in EGFR in 9 pts, including mutations located in the exon 20 loop following the C-helix (6), T790M (5), and D379E (1). Conclusions: Concordance between tissue and plasma ctDNA for EGFR ex20ins mutations at BL was 76%. EGFR ex20ins VAF decreased significantly after 2 treatment cycles in mobocertinib-treated patients with PR and SD. Plasma ctDNA longitudinal monitoring may be useful to assess mutation status and disease progression in pts with NSCLC treated with mobocertinib. Clinical trial information: NCT02716116. [Table: see text]
IMMU-01. Combining CD28 and 4-1BB costimulation<i>in trans</i> enhances the anti-glioma efficacy and persistence of B7-H3 CAR T cells in immune-competent brain tumor models
Authors: Dalia Haydar, Abdul Elayan, Zhongzhen Yi, Stephen Gottschalk, Chris DeRenzo, Giedre Krenciute
Journal: Neuro-Oncology (2022)

Abstract We and others have demonstrated that B7-H3 CAR T-cells have potent antitumor responses in xenograft models for brain tumors; however, these models do not recapitulate the immunosuppressive tumor microenvironment (TME) in patients with high-grade glioma. To evaluate the safety and efficacy of antigen-specific CAR T-cells, we adapted the immune-competent GL261 glioma model which recapitulates human disease and host immune barriers. We generated a library of B7-H3 CARs with different transmembrane (CD8, CD28), costimulatory (CD28, 4-1BB), and activation (ζ, mutζ) domains. We then compared their cytolytic activity, expansion, and anti-tumor activity. Results show that B7-H3 CARs with CD28 transmembrane and costimulatory domains have superior efficacy compared to CARs with CD8 and 4-1BB domains. Additionally, CARs with mutated ζ activation domain have better overall persistence. However, providing costimulation signals through CD28 or 4-1BB alone does not induce superior anti-glioma efficacy of B7-H3 CAR T-cells in vivo. Thus, we next investigated whether incorporating 4-1BB signaling into CD28-based CARs using in trans design enhances the therapeutic efficacy of B7-H3 CAR T-cells. We found that in repeat stimulation assays, surface expression of 4-1BBL enhanced expansion of B7H3 CAR T-cells at least 300-folds more than T-cells with CD28 or 4-1BB costimulatory domains alone. Additionally, 4-1BBL expression significantly enhanced the sequential killing capacity compared to CD28- or 41BB-based B7-H3 CAR T-cells. High dimensional flow cytometry analysis of GL261 tumors post CAR T-cell injection revealed unique immune clusters including dendritic cells and lymphoid predominant populations in mice treated with 4-1BBL expressing CARs. Thus, expression of 4-1BBL on CD28-based CARs reshaped the TME and enhanced persistence and anti-glioma efficacy of B7-H3 CAR T-cells. Studies examining transcriptional and epigenetic programs, and TME/CAR T-cell interactions are in progress. Results will define pathways that dictate CAR T-cell performance and will identify unique mechanisms for further improvements utilizing other members of TNF-superfamily.
Bio-miR: A prognostic microRNA-based signature for localized clear cell renal cell carcinoma.
Authors: Alvaro Pinto, Lucía Trilla-Fuertes, Jesus Miranda Poma, Naveen Vasudev, Eugenia García-Fernández, Rocio Lopez Vacas, Natalia Miranda, Michelle Wilson, Elena López-Camacho, Ana Pertejo, Maria Isabel Lumbreras-Herrera, Joanne C Brown, Andrea Zapater-Moros, Guillermo De Velasco, Daniel E. Castellano, María Pilar González-Peramato, Enrique Espinosa, Rosamonde Banks, Juan Angel Fresno-Vara, Angelo Gámez-Pozo
Journal: Journal of Clinical Oncology (2022)

e16519 Background: Prognosis of localized clear cell renal cell carcinoma (ccRCC) patients is estimated by nomograms based on clinico-pathological factors. However, clinical guidelines do not recommend their use. Recently, pembrolizumab has demonstrated benefit in disease-free survival (DFS) in medium-high risk localized ccRCC, increasing the need for better patient stratification tools. In this study, we have defined and validated a molecular signature, Bio-miR, based on the expression of nine microRNAs, with prognostic value in ccRCC. Methods: The discovery and two validation cohorts (Leeds-UK and Spain) consisted of patients with resected localized (stage Ib-III) ccRCC and no adjuvant therapy. miRNA expression was analyzed using microarrays and validated using qPCR in FFPE nephrectomy tissues. Cox regression was used to define the best microRNAs combination to predict risk of relapse. Results: In the discovery cohort (n = 71), DFS at 5 years was 93.9% amongst Bio-miR-defined low-risk patients and 61.6% in high-risk patients (HR = 6.9 (3.4-42.9), p &lt; 0.001). Cancer-specific survival at 5 years was 95.7% and 86.4% in low- and high-risk patients, respectively (HR = 7.7 (1.7-35.1), p &lt; 0.01). Bio-miR compared favorably with different histopathological factors and UISS and Karakiewicz´s nomograms. In the Leeds validation cohort (n = 75/95 passing qPCR quality control), patients defined as low-risk had a 5-year DFS rate of 94% versus 62% in high-risk defined disease. In this cohort Bio-miR was able to divide the Leibovich intermediate-risk population into two groups with divergent five-year DFS rates (100% vs 71%). In the Spanish validation cohort (n = 180), DFS rates at 5 years were 82.9% in the low-risk group and 58.7% in the high-risk group (HR = 2.4 (1.4-4.4); p &lt; 0.005). Applying the inclusion criteria from the phase III KEYNOTE-564 trial, Bio-miR identifies a small low-risk population who could be spared adjuvant treatment. Conversely, amongst patients excluded from the study due to low-risk features, Bio-miR defines a high-risk population (DFS at five years of 50%) who should be prioritized for adjuvant therapy. Conclusions: We define and validate a nine-microRNA based signature capable of dichotomizing patients with localized ccRCC into low- and high-risk groups based on risk of relapse. Importantly, Bio-miR acts independently of tumor stage and grade and could, therefore, help refine the selection of patients for adjuvant therapy as well as inform the design of future adjuvant ccRCC trials.
NFB-14. Post-operative use of MEK inhibitors to prevent rebound growth following partial resection of plexiform neurofibromas
Authors: Priya Chan, Molly Hemenway, Kathleen McMahon, Nathan Dahl, Leahthan Domeshek, Brooke French, Nicholas Foreman
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Plexiform neurofibromas (PNs) can cause significant morbidity leading to functional impairment, pain, and disfigurement. Management of PNs is challenging. Complete surgical resection is often not possible due to tumor growth along vital structures, and rebound growth is frequently experienced with partially resected PNs. The mitogen-activated protein kinase pathway has been implicated in the growth of PNs, and MEK1/2 inhibitors have been shown to be an effective treatment of PNs. OBJECTIVE: To describe our institutional experience using post-operative MEK1/2 inhibitors in the treatment of pediatric patients with PNs following subtotal resection (STR). METHODS: A single-institution retrospective record review. RESULTS: A total of 35 patients had STR of their PN. Fourteen patients underwent resection alone, ten patients received adjuvant mechanistic target of rapamycin (mTOR) inhibitors and eleven patients received adjuvant MEK1/2 inhibitors. The mean follow-up time was 5.1 years, but relatively shorter for patients receiving adjuvant MEK1/2 inhibitors. Mean time from resection to start of adjuvant therapy and mean duration of adjuvant therapy for patients in the mTOR inhibitor group was 3.3 weeks and 3.9 months, respectively, and for patients in the MEK1/2 inhibitor group was 3.1 weeks and 8.5 months, respectively. The number of patients in each group requiring additional treatment with surgical resection or medical therapy, was 11 of 14 patients (78.6%) in the resection only group, 7 of 10 patients (70%) in the adjuvant mTOR inhibitor group and 3 of 11 patients (27.3%) in the adjuvant MEK1/2 inhibitor group. CONCLUSIONS: A short course of MEK1/2 inhibitors following subtotal resection of PNs is effective in the short term in preventing rebound growth when compared to STR alone or adjuvant mTOR inhibitors. Treatment is well tolerated and should be considered as adjuvant therapy in pediatric patients. Long-term follow-up is necessary to judge the effectiveness of this approach.
Hypoxia-inducible factors: master regulators of hypoxic tumor immune escape
Authors: Qinghua Wu, Li You, Eugenie Nepovimova, Zbynek Heger, Wenda Wu, Kamil Kuca, Vojtech Adam
Journal: Journal of Hematology & Oncology (2022)

Hypoxia, a common feature of the tumor microenvironment in various types of cancers, weakens cytotoxic T cell function and causes recruitment of regulatory T cells, thereby reducing tumoral immunogenicity. Studies have demonstrated that hypoxia and hypoxia-inducible factors (HIFs) 1 and 2 alpha (HIF1A and HIF2A) are involved in tumor immune escape. Under hypoxia, activation of HIF1A induces a series of signaling events, including through programmed death receptor-1/programmed death ligand-1. Moreover, hypoxia triggers shedding of complex class I chain-associated molecules through nitric oxide signaling impairment to disrupt immune surveillance by natural killer cells. The HIF-1-galactose-3-O-sulfotransferase 1-sulfatide axis enhances tumor immune escape via increased tumor cell-platelet binding. HIF2A upregulates stem cell factor expression to recruit tumor-infiltrating mast cells and increase levels of cytokines interleukin-10 and transforming growth factor-β, resulting in an immunosuppressive tumor microenvironment. Additionally, HIF1A upregulates expression of tumor-associated long noncoding RNAs and suppresses immune cell function, enabling tumor immune escape. Overall, elucidating the underlying mechanisms by which HIFs promote evasion of tumor immune surveillance will allow for targeting HIF in tumor treatment. This review discusses the current knowledge of how hypoxia and HIFs facilitate tumor immune escape, with evidence to date implicating HIF1A as a molecular target in such immune escape. This review provides further insight into the mechanism of tumor immune escape, and strategies for tumor immunotherapy are suggested.
Engineered meatballs via scalable skeletal muscle cell expansion and modular micro-tissue assembly using porous gelatin micro-carriers
Authors: Ye Liu, Rui Wang, Shijie Ding, Liping Deng, Yuanyuan Zhang, Junyang Li, Ziao Shi, Zhongyuan Wu, Kaini Liang, Xiaojun Yan, Wei Liu, Yanan Du
Journal: Biomaterials (2022)
Electronic research consents for complex early-phase I-II clinical trials integrated with telemedicine visits compared with in-person encounters.
Authors: Michael T. Buckley, Molly O'Shea, Allison Lipitz-Snyderman, Gilad Kuperman, Suken Shah, Yael Redelman-Sidi, Joseph M. Lengfellner, Stephanie Lucia Terzulli, Collette Houston, Paul Sabbatini
Journal: Journal of Clinical Oncology (2022)

1514 Background: Based on our previous research with patient satisfaction for electronic consenting (95% of 940 respondents would recommend it another patient), we hypothesized that telemedicine (telemed) would be received as well as or better than in-person clinical research (CR) consent encounters for complex early-phase clinical trial (Phase I-II) and clinical genetic consent discussions by patients. Oncologist experiences to date have shown that telemed works well for uncomplicated clinical scenarios, but its performance alongside increased care complexity is less clear from the patient perspective. Methods: We conducted a one-time survey of adult patients having a telemed consent visit between 8/31/21 and 2/13/22 and an in-person clinic visit. Nine CR specific questions covered visit preference and empowerment across 6 high value consent agency domains. Results: 513 patients completed the survey and consented across 96 Clinical trials (CT), including genetic, therapeutic, diagnostic, and quality of life. Consent discussions were performed by 75 clinicians and 41 non-clinicians, with the majority (64%) for clinical genetic and Phase I-II CTs. Most patients (52%) preferred telemed over in-person clinic visits (19%) when all visit related factors (time, cost, convenience, quality of care, healthcare team interaction) were considered ( P&lt;.05) (Table). Comparing their last in-person visit with telemed, patients reported feeling either less stressed/overwhelmed (16%) for their consent discussion or about the same (39%) using telemed, and 6% were more stressed ( P&lt;.05). Patients expressed equal comfort taking agency-supported action across 6 domains regardless of consent setting. Conclusions: Electronic consenting via telemed is the preferred method for consent in complex early-phase clinical trials when all visit factors are considered and performs as well across 6 key agency domains when compared with in-person visits. Telemed does not contribute additional stress to consent appointments for most patients and performs well across complex clinical genetic and Phase I-II clinical trial discussions. Our findings suggest telemed and electronic consent should be offered as an option for patients throughout their treatment continuum. Beyond MSK, our data support a broader call for organizations to offer telemed platforms for CT discussions to increase overall patient satisfaction and potentially increase participation. [Table: see text]
Txagorrapid: Ultrarapid infusion in 30 minutes of the biosimilar of rituximab truxima—A cohort study.
Authors: Ernesto Perez Persona, Laida Cuevas Palomares, Ariane Unamunzaga Cilaurren, Xabier Gutierrez López de Gutierrez, Buenaventura Buendía Ureña, Carmen Luisa Molinillo Fernández, Begoña Benito Ibarrondo, Ana Isabel Cordero Osua, Beatriz Benítez Delgado, Miguel Angel Andrés Moralejo, Juan José García Albás, José María Guinea de Castro
Journal: Journal of Clinical Oncology (2022)

e13638 Background: Rituximab (anti-CD20 Ab) is the cornerstone of the treatment of non-Hodgkin B lymphomas. Infusion-related reactions (IRR) are the most common adverse effects. To reduce them, intravenous premedication with antihistamine and acetaminophen is administered prior to rituximab. If no IRR after first infusion, subsequent infusions time takes 3-6 hours. Many centers use the rapid 90-minute infusion (off-label). Since 2017 subcutaneous rituximab formulation is available, that takes 5 minutes of administration. Nevertheless, in order to reduce cost, due to approval of biosimilars, some health providers continue using intravenous rituximab. On the other hand, with COVID pandemic, an effort to reduce visits and day-care hospitals stays has been made. In the current situation, it would be convenient to reduce day-care stay and the nursing care burden. We wanted to evaluate the safety of an ultrarapid infusion of biosimilar rituximab in a total time of 30 minutes by analyzing IRR and adverse events (AE). Methods: Since November 2021, 3 cohorts of ultrafast infusion have been studied as follows: One cohort (Cohort 1) with intravenous premedication with dexchlorpheniramine and acetaminophen, followed by rituximab infusion over 1 hour, and 2 cohorts with rituximab infusion over 30 minutes: Cohort 2: with intravenous premedication, and cohort 3 with oral premedication. IRR and adverse events have been independently reviewed and graded using Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (November 27, 2017). Results: 34 patients have been included receiving 48 rituximab infusions (16 infusions in each cohort). Median age was 64 years old (range: 51-91). Diagnostic of NHL were as follows: large b cell: 10; follicular: 13; marginal: 7; mantle cell: 1, Waldeström: 1; Ritcher transformation: 2. Rituximab infusion was in monotherapy (21), and in combination (27) with: bendamustine: 9, CHOP: 17, GEMOX: 1. Considering safety, no IRR has been observed in cohort 1 (1 hour infusion), and 1 IRR grade II in cohort 3 (30 minutes, oral premedication). Other AE were: hypertension grade I and hypotension grade I, both in cohort 2. Conclusions: Ultrarapid rituximab infusion is safe. Oral premedication is feasibly allowing a total infusion time of 30 minutes. This infusion rate alleviates day-care burden saving between 75-90% of time in each rituximab infusion, reduce day-care stay and is comfortable for the patients. Clinical trial information: NCT05191225.